Peripheral artery disease (PAD) affects 9 to 12 million Americans [1] and 1.5 million will require an intervention (407,400 receive bypass or amputation;1,080,000 receive angioplasty, stent or atherectomy) each year [3]. Unfortunately, only one-third of patients have a patent artery one year after balloon angioplasty of the femoral artery [4]. Bare metal stents [5-7] have eliminated elastic recoil and flow-limiting dissections bu have not significantly impacted restenosis due to intimal hyperplasia [3, 8-10]. Indeed, stents placed in the femoro- popliteal segment provide patency rates of only 54-63% at 1 year and 28-55% at 2 years [5, 7, 11-12], and drug eluting stents have fared no better than bare stents in eliminating restenosis [13-15]. Recently, use of drug-coated balloons in the peripheral artery has shown potential to improve patency without the need to implant stents [16]. However, the kinetics of luminal-based therapy (drug-eluting balloons and stents) place the maximal concentration of drug at the luminal-wall interface. This has the distinct disadvantage of hindering healing and re-endothelialization of the vessel. Recent data suggests that the adventitia plays a critical role in intimal hyperplasia, contributing to both neointimal cell volum and adverse remodeling. We have successfully completed the aims of Phase 1 research and in pre-clinical studies we have demonstrated non-toxic, efficacious doses of rapamycin, a well-known anti-restenotic agent in a novel nanoparticle formulation, delivered directly into the vascular adventitia through a percutaneous catheter at the time of angioplasty. This method avoids foreign body implantation and creates a high concentration in the adventitia and a lower concentration at the luminal surface. Mercator MedSystems has developed a catheter that slides a single needle through the vessel wall when a balloon is inflated, allowing direct therapeutic access to the adventitia. The catheter has been used in human pilot studies with successful adventitial delivery leading to cylindrical deposition of drugs around the vessel, creating a natural drug-eluting reservoir. We are now proposing to advance this research into human clinical trials, with Specific Aims of confirming safety while demonstrating the positive biological effect and clinical benefits of rapamycin delivered to the adventitia at the time of peripheral artery angioplasty. The innovative product that will be developed in this proposal is a combination device/drug therapy that will be broadly applicable to vascular disease. We believe that the significance of this proposal lies in the fact that (a) we are addressing a recalcitrant clinical problem (b) perivascular or adventitial therapy may be used as an adjunct to several common interventional revascularization techniques and (c) therapeutic success in PAD could be rapidly translated to settings such as coronary and renal artery restenosis or restenosis following coronary and peripheral bypass grafting. If these Phase 2 studies are successful, we intend to move into pivotal clinical trials and ultimately seek FDA approval for a novel combination product.

Public Health Relevance

The changing demographics of Western societies include an aging population with a near epidemic of obesity, insulin resistance, and diabetes mellitus, causing a dramatic rise in the prevalence of PAD, which impairs the ability to walk and causes pain, nonhealing ulcers and gangrene in the lower extremities. It is a significant public health burden and, at its worst, leads to leg amputations. Among individuals most severely affected, revascularization of the lower extremities to restore circulation is the most effective therapy. However, to date, there has been no effective pharmaceutical strategy to reduce the incidence of restenosis due to intimal hyperplasia in peripheral arteries. Therefore, the relevance of this proposal lies in its potential to improve patency of lower extremity interventions, reduce morbidity, and reduce the significant financial burden currently associated with the treatment of peripheral artery disease (PAD).